Stem Cell Reviews and Reports

, Volume 14, Issue 3, pp 451–460 | Cite as

Human Adipose Tissue Stem Cells Promote the Growth of Acute Lymphoblastic Leukemia Cells in NOD/SCID Mice

  • Myoung Woo Lee
  • Yoo Jin Park
  • Dae Seong Kim
  • Hyun Jin Park
  • Hye Lim Jung
  • Ji Won Lee
  • Ki Woong Sung
  • Hong Hoe Koo
  • Keon Hee Yoo


In this study, the effect of adipose tissue stem cells (ASCs) on the growth of acute lymphoblastic leukemia (ALL) cells was examined in an in vivo model. We established ALL cell lines expressing firefly luciferase (ALL/fLuc) by lentiviral infection that were injected intraperitoneally to NOD/SCID mice. The luciferase activities were significantly higher in mice co-injected with 105 ALL/fLuc cells and ASCs than in those injected with ALL/fLuc cells alone. Co-injection of 105 ALL/fLuc cells and ASCs in differing ratios into mice gradually increased the bioluminescence intensity in all groups, and mice co-injected with 1 or 2 × 106 ASCs showed higher bioluminescence intensity than those receiving lower numbers. Interestingly, in the mice injected with 105 or 107 ALL/fLuc cells alone, the formation of tumor masses was not observed for at least five weeks. Moreover, co-injection of 107 ALL/fLuc cells and 5 × 105 ASCs into mice increased the bioluminescence intensity in all groups, and showed significantly higher bioluminescence intensity compared to mice co-injected with human normal fibroblast HS68 cells. Overall, ASCs promote the growth of ALL cells in vivo, suggesting that ASCs negatively influence hematologic malignancy, which should be considered in developing cell therapy using ASCs.


Adipose tissue stem cell Acute lymphoblastic leukemia Firefly luciferase Cell proliferation Cell therapy 



This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2017R1D1A1B03027984] and by the Ministry of Science, ICT and Future Planning [2013R1A2A2A01067331 and 2017R1A2B4008716], Republic of Korea.

Compliance with Ethical Standards

Conflict of Interest

The authors report no potential conflicts of interest.

Supplementary material

12015_2018_9806_MOESM1_ESM.docx (183 kb)
Supplementary material 1 (DOCX 182 KB)


  1. 1.
    Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., Schwartz, R. E., Keene, C. D., Ortiz-Gonzalez, X. R., et al. (2002). Pluripotency of mesenchymal stem cell derived from adult marrow. Nature, 418(6893), 41–49.CrossRefPubMedGoogle Scholar
  2. 2.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411), 143–147.CrossRefPubMedGoogle Scholar
  3. 3.
    Young, H. E., Steele, T. A., Bray, R. A., Hudson, J., Floyd, J. A., Hawkins, K., et al. (2001). Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. The Anatomical Record, 264(1), 51–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Zuk, P. A., Zhu, M., Mizuno, H., Huang, J., Futrell, J. W., Katz, A. J., et al. (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering, 7(2), 211–228.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang, H. S., Hung, S. C., Peng, S. T., Huang, C. C., Wei, H. M., Guo, Y. J., et al. (2004). Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells, 22(7), 1330–1337.CrossRefPubMedGoogle Scholar
  6. 6.
    Erices, A., Conget, P., & Minguell, J. (2000). Mesenchymal progenitor cells in human umbilical cord blood. British Journal of Haematology, 109(1), 235–242.CrossRefPubMedGoogle Scholar
  7. 7.
    Amado, L. C., Saliaris, A. P., Schuleri, K. H., St John, M., Xie, J. S., Cattaneo, S., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 102(32), 11474–11479.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    van Poll, D., Parekkadan, B., Cho, C. H., Berthiaume, F., Nahmias, Y., Tilles, A. W., et al. (2008). Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology, 47(5), 1634–1643.CrossRefPubMedGoogle Scholar
  9. 9.
    Li, L., Hui, H., Jia, X., Zhang, J., Liu, Y., Xu, Q., et al. (2016). Infusion with human bone marrow-derived mesenchymal stem cells improves β-cell function in patients and non-obese mice with severe diabetes. Scientific Reports, 6, 37894.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nakamizo, A., Marini, F., Amano, T., Khan, A., Studeny, M., Gumin, J., et al. (2005). Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Research, 65(8), 3307–3318.CrossRefPubMedGoogle Scholar
  11. 11.
    Khakoo, A. Y., Pati, S., Anderson, S. A., Reid, W., Elshal, M. F., Rovira, I. I., et al. (2006). Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. Journal of Experimental Medicine, 203(5), 1235–1247.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Klopp, A. H., Gupta, A., Spaeth, E., Andreeff, M., & Marini, F. (2011). Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells, 29(1), 11–19.CrossRefPubMedGoogle Scholar
  13. 13.
    Luo, J., Lee, S. O., Cui, Y., Yang, R., Li, L., & Chang, C. (2015). Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals. Oncotarget, 6(29), 27555–27565.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Maestroni, G., Hertens, E., & Galli, P. (1999). Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. Cellular and Molecular Life Sciences, 55(4), 663–667.CrossRefPubMedGoogle Scholar
  15. 15.
    Qiao, L., Xu, Z., Zhao, T., Ye, L., & Zhang, X. (2008). Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Letters, 269(1), 67–77.CrossRefPubMedGoogle Scholar
  16. 16.
    Song, N., Gao, L., Qiu, H., Huang, C., Cheng, H., Zhou, H., et al. (2015). Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant. International Journal of Molecular Medicine, 36(1), 139–149.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liang, R., Huang, G. S., Wang, Z., Chen, X. Q., Bai, Q. X., Zhang, Y. Q., et al. (2008). Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. International Journal of Hematology, 87(2), 152–166.CrossRefPubMedGoogle Scholar
  18. 18.
    Nwabo Kamdje, A. H., Mosna, F., Bifari, F., Lisi, V., Bassi, G., Malpeli, G., et al. (2011). Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood, 118(2), 380–389.CrossRefPubMedGoogle Scholar
  19. 19.
    Manabe, A., Coustan-Smith, E., Behm, F. G., Raimondi, S. C., & Campana, D. (1992). Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood, 79(9), 2370–2377.PubMedGoogle Scholar
  20. 20.
    Wu, K. N., Zhao, Y. M., He, Y., Wang, B. S., Du, K. L., Fu, S., et al. (2014). Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways. Leukemia & Lymphoma, 55(3), 668–676.CrossRefGoogle Scholar
  21. 21.
    Takam Kamga, P., Bassi, G., Cassaro, A., Midolo, M., Di Trapani, M., Gatti, A., et al. (2016). Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia. Oncotarget, 7(16), 21713–21727.PubMedGoogle Scholar
  22. 22.
    Secchiero, P., Zorzet, S., Tripodo, C., Corallini, F., Melloni, E., Caruso, L., et al. (2010). Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PLoS One, 5(6), e11140.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhu, Y., Sun, Z., Han, Q., Liao, L., Wang, J., Bian, C., et al. (2009). Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia, 23(5), 925–933.CrossRefPubMedGoogle Scholar
  24. 24.
    Ramasamy, R., Lam, E. W., Soeiro, I., Tisato, V., Bonnet, D., & Dazzi, F. (2007). Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia, 21(2), 304–310.CrossRefPubMedGoogle Scholar
  25. 25.
    Sasaki, M., Abe, R., Fujita, Y., Ando, S., Inokuma, D., & Shimizu, H. (2008). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. Journal of Immunology, 180(4), 2581–2587.CrossRefGoogle Scholar
  26. 26.
    Toma, C., Pittenger, M. F., Cahill, K. S., Byrne, B. J., & Kessler, P. D. (2002). Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 105(1), 93–98.CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang, M., Mal, N., Kiedrowski, M., Chacko, M., Askari, A. T., Popovic, Z. B., et al. (2007). SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB Journal, 21(12), 3197–3207.CrossRefPubMedGoogle Scholar
  28. 28.
    Caplan, A. I., & Dennus, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98(5), 1076–1084.CrossRefPubMedGoogle Scholar
  29. 29.
    Ho, I. A., Toh, H. C., Ng, W. H., Teo, Y. L., Guo, C. M., Hui, K. M., et al. (2013). Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells, 31(1), 146–155.CrossRefPubMedGoogle Scholar
  30. 30.
    Tian, K., Yang, S., Ren, Q., Han, Z., Lu, S., Ma, F., et al. (2010). p38 MAPK contributes to the growth inhibition of leukemic tumor cells mediated by human umbilical cord mesenchymal stem cells. Cellualr Physiology and Biochemistry, 26(6), 799–808.CrossRefGoogle Scholar
  31. 31.
    Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105(4), 1815–1822.CrossRefPubMedGoogle Scholar
  32. 32.
    Nauta, A. J., & Fibbe, W. E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood, 110(10), 3499–3506.CrossRefPubMedGoogle Scholar
  33. 33.
    Kinnaird, T., Stabile, E., Burnett, M. S., Lee, C. W., Barr, S., Fuchs, S., et al. (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research, 94(5), 678–685.CrossRefPubMedGoogle Scholar
  34. 34.
    Wu, Y., Chen, L., Scott, P. G., & Tredget, E. E. (2007). Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells, 25(10), 2648–2659.CrossRefPubMedGoogle Scholar
  35. 35.
    Panayiotidis, P., Jones, D., Ganeshaguru, K., Foroni, L., & Hoffbrand, A. V. (1996). Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. British Journal of Haematology, 92(1), 97–103.CrossRefPubMedGoogle Scholar
  36. 36.
    Lagneaux, L., Delforge, A., Bron, D., De Bruyn, C., & Stryckmans, P. (1998). Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood, 91(7), 2387–2396.PubMedGoogle Scholar
  37. 37.
    Garrido, S. M., Appelbaum, F. R., Willman, C. L., & Banker, D. E. (2001). Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Experimental Hematology, 29(4), 448–457.CrossRefPubMedGoogle Scholar
  38. 38.
    Konopleva, M., Konoplev, S., Hu, W., Zaritskey, A., Afanasiev, B., & Andreeff, M. (2002). Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia, 16(9), 1713–1724.CrossRefPubMedGoogle Scholar
  39. 39.
    Naderi, E. H., Skah, S., Ugland, H., Myklebost, O., Sandnes, D. L., Torgersen, M. L., et al. (2015). Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death. Molecular Cancer, 14(1), 14.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zhang, X., Tu, H., Yang, Y., Wan, Q., Fang, L., Wu, Q., et al. (2016). High IL-7 levels in the bone marrow microenvironment mediate imatinib resistance and predict disease progression in chronic myeloid leukemia. International Journal of Hematology, 104(3), 358–367.CrossRefPubMedGoogle Scholar
  41. 41.
    Han, Y., Wang, Y., Xu, Z., Li, J., Yang, J., Li, Y., et al. (2013). Effect of bone marrow mesenchymal stem cells from blastic phase chronic myelogenous leukemia on the growth and apoptosis of leukemia cells. Oncology Reports, 30(2), 1007–1013.CrossRefPubMedGoogle Scholar
  42. 42.
    Pramanik, R., Sheng, X., Ichihara, B., Heisterkamp, N., & Mittelman, S. D. (2013). Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy. Leukemia Research, 37(5), 503–509.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Stem Cell & Regenerative Medicine InstituteSamsung Medical CenterSeoulSouth Korea
  3. 3.Department of Health Sciences and Technology, SAIHSTSungkyunkwan UniversitySeoulSouth Korea
  4. 4.Department of Medical Device Management and Research, SAIHSTSungkyunkwan UniversitySeoulSouth Korea

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